WO1996016938A1 - Indole derivative - Google Patents

Abstract

An indole derivative represented by general formula (1) and a salt thereof, wherein R1 represents lower alkoxy, lower alkoxycarbonyl lower alkoxy, carboxy lower alkoxy, lower alkoxycarbonyl, phenyl lower alkoxy, optionally hydroxylated lower alkyl, di(lower alkyl)amino-sulfonyl, etc.; R2 represents hydrogen, halogeno, lower alkoxy, lower alkoxycarbonyl lower alkoxy, carboxy lower alkoxy, etc.; R3 represents hydrogen or lower alkyl; R4 represents halogeno or trifluoromethyl; and R5 represents lower alkyl. The compound is a potent β3 adrenergic receptor stimulant with a high selectivity, and is useful as a preventive or remedy for obesity, diabetes, etc.

Description

 Harm

 Indole derivative

Technical field

The present invention is excellent in selectivity, strong) novel Indoru derivatives have the S ₃ Adorenarin receptor stimulating effect.

Background art

A ^ receptors sympathetic, and; 5 two subtypes of ₂ are known to exist. Currently, A Dorenari emissions receptor stimulant as cardiac function enhancers or vasopressors, β ₂ Ύ Dorenarin receptor agonists have been clinically used respectively as a bronchodilator.

Recently, a third adrenergic receptor has been isolated as a third subtype distinct from these two subtypes [Emorine, LJ. Et al .: Science, 245. 11 1 18—1 1 2 1 ( 1 989)]. The) S ₃ adrenergic receptors are present in brown adipose cells, it is believed to have a function of increasing the particular good connexion heat-producing ability to degrade lipids white adipose tissue attached like subcutaneously or inner knee, obesity One of the causes of the disease has been suggested to be related to ^ ₃ adrenergic receptor. Also it has been reported related with the Insurin-independent diabetes onset and 9 ₃ Adorenarin receptors.

/ 3 When ₃ adrenergic receptor stimulants also act on or S ₂ adrenergic receptor subtypes, side effects can include hypercardiac function or limb tremor. Therefore, there is a demand for a compound that has a strong S ₃ adrenergic receptor stimulating action and that does not stimulate the S ₂ adrenergic receptor or has a low degree of stimulation of these receptors. In the present specification, such a compound is sometimes referred to as “a compound having excellent selectivity”. / 9 As a drug that stimulates ₃ adrenergic receptors, for example, BRL 3513 5C (R * .R *) — (±) — [4-1 [2- [2- (3-clofenphenyl) 1-2-hydrin] [Xicetylamino] propyl] phenoxy] acetic acid methyl ester hydrobromide; Japanese Patent Publication No. 63-26744 and European Patent No. 23385] and SR-58611 A [(R.S) -N- (7- Ethkin carbonyl methoxy 1,2,3,4-tetrahydronaphth-1-inole) -12- (3-chlorophenyl) -12-hydroxyquinethanamine hydrochloride; Japanese Patent Publication No. 64-66152 and European Patent Application Publication No. 255415] is known. However, these BRL 35135 and SR-58611A are different from the compounds of the present invention described below in that they are not indole derivatives.

 Indole derivatives listed in Table 1 below are known.

-9- table 1

しかし、 これらの化合物は、 そのベンゼン環上に 2つの置換基を有する 点およびインドール環上に置換基を持たない点で、 後述の本発明化合物と は異なった化学構造を有している。 しかも、 これらの先行文献のいずれに も 3₃アドレナリン受容体刺激作用を示唆するような開示はなされていな い。

However, these compounds have different chemical structures from the compounds of the present invention described below in that they have two substituents on the benzene ring and do not have a substituent on the indole ring. Moreover, even 3 ₃ disclosure as to suggest adrenergic effects have such have been made in any of these prior art documents.

 The following compounds are known as compounds having a chemical structure similar to the compound of the present invention than the compounds listed in Table 1 above.

For example, the following compound A is described in J. Pharma. Pharmacol., 17, 742-746 (1965). -NH-CH ₂ — CH

--II II J Compound A

The following compound B is described in Acta Polon. Pharm., 38, 407-410 (198 l) (Chem. Abstr., 96, 142543k (l 982)). Compound

The above compounds A and B in that no substituent R ₅ in the present invention compounds of points and later no substituent on the benzene ring, the present invention of compounds have different chemical structure I have. Moreover, none of these documents mentions the pharmacological effects of the compounds A and B.

 Furthermore, Chem. Abstr., 109, 128763 n (1988) describes an N-indolylalkylamino-1-aryl substituted alkanol derivative represented by the following formula [VIII].

R- [VIII]

[In the formula, R is a phenyl group, an m- or p-ditrophenyl group, and R ¹ is a hydrogen atom or a methyl group.] This compound has a different chemical structure from the below-mentioned compound of the present invention in that the substituent on the benzene ring is a dinitro group and that it has no substituent on the indole ring. The formula [VIII] specifically includes the following compound C.

N0 ₂

本発明化合物は、 上記化合物 A、 Bおよび Cに比べて後記試験例に示さ れるように、 β ₃了ドレナリン受容体刺激薬としてはるかに優れている。 従って、 本発明の目的の 1つは、 選択性に優れた、 強い ァ ドレナリ ン受容体刺激作用を有する新規ィンドール誘導体およびその塩を提供する ことである。 J-Compound C

The compounds of the present invention, as shown in later test examples as compared with the compounds A, B and C, are far superior as a beta ₃ Ryo Dorenarin receptor stimulants. Therefore, one of the objects of the present invention is to provide a novel indole derivative having excellent selectivity and a strong adrenergic receptor stimulating action, and a salt thereof.

Disclosure of the invention

 The present invention relates to an indole derivative represented by the following formula [I] and a salt thereof.

[Wherein, is a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or the following ( a) to (d) or a methylenedioxy group together with R ₂ , The alkoxy group may be substituted with a carboxyl group or a lower alkoxycarbonyl group.

 (a) group represented by the formula X-Ra

 (Where X is 0, S or NH, Ra is a hydrogen atom or a lower alkyl group, provided that when X is S, Ra is a lower alkyl group)

 Rb

 I

(b) a group represented by the formula [0 (CH ₂ ) m—CH] n—Rbb

 (Where Rb is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a carboxyl group, Rbb is a lower alkoxycarbonyl group or a carboxyl group, m is an integer of 0 to 3, and n is an integer of 0 or 1. )

(c) a group represented by formula 1 0 (CH ₂ ) p—Rc

 (Where Rc is a lower alkanoyl group, a hydroxyl group, a cyano group, a phenyl group, a mono- or di-lower alkylaminocarbonyl group, or a compound represented by the following formula:

0

 II

— P-OR _A

 OR A

(Where _RA is a hydrogen atom or a lower alkyl group)

Where p is an integer from 1 to 4.)

(d) a group represented by the formula: Y— (CH ₂ ) q—Rd

 (Where Y is NH or S, Rd is a carboxyl group or a lower alkoxycarbonyl group, and q is an integer of 1-4)

R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a hydroxy group, a hydroxy group, a lower alkoxy group, or the above (b) Or means the same group as (c), or forms a methylenedioquine group with R, as described above, and the methylenedioxy group may be substituted with a carboxyl group or a lower alkoxycarbonyl group;

R ₃ represents a hydrogen atom or a lower alkyl group,

 W is the following formula U I bonded to the 2- or 3-position of the indole ring of the general formula [I]

R ₄

^ -CH-CH ₂ -NH-CH-CH ₂ — [II] 0 ^H R ₅

(Where R ₄ is a halogen atom or a trifluoromethyl group, and R ₅ is a lower alkyl group)

Means a group represented by

 The structural feature of the compound of the present invention is represented by the general formula (I):

 (1) The substituent W has a specific atom or group at the 3-position of the benzene ring.

(2) The substituent R ₅ is a lower alkyl group

 (3) Having a specific substituent and R 2 at the 4- to 7-positions of the indole ring

(4) The substituent W is bonded to the indole ring at the 2- or 3-position.

The strong stimulating action and excellent selectivity of the compounds of the present invention on the _3- adrenergic receptor are based on these structural combinations.

 The terms used in this specification are described below.

A group with the term "lower" means that the group has 1-4 carbon atoms. Specific examples of “lower alkyl group” include methyl, ethyl, and methyl. Mouth pill, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are preferred, but methyl, ethyl, propyl and isopropyl are preferred. Specific examples of the “lower alkyl group substituted with a hydroxyl group” include hydroxymethyl, 2-hydroxyxethyl and the like. Specific examples of the “lower alkylsulfonylamino group” include methylsulfonylamino, ethylsulfonylamino and the like. Specific examples of the “mono- or di-lower alkylaminosulfonyl group” include monomethylaminosulfonyl, dimethylaminosulfonyl, monoethylaminosulfonyl, acetylaminosulfonyl and the like. Specific examples of the “lower alkoxycarbonyl group” include methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Specific examples of the “lower alkanoyl group” include acetyl, propionyl and the like. Specific examples of the “mono or di-lower alkylaminocarbonyl group” include methylaminocarbonyl, dimethylaminocarbonyl, methylethylaminocarbonyl and the like. “Halogen atom” means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, and particularly preferably fluorine or chlorine. Specific examples of the “lower alkoxy group” include methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Specific examples of the “lower alkoxycarbonyl lower alkoxy group” include methoxycarbonyl methoxy, 1-methoxycarbonylethoxy, 2-methoxycarbonylethoxy, 1-methoxycarbonylpropoxy, and 3-methoxy. Carbonylpropoxy and the like. Specific examples of the “carboxy lower alkoxy group” include carboxymethoxy, 1-carboquinethoxy, 2-carboquinethoxy, 1-carboxypropoxy, 3-carboxypropoxy, and the like. "Fueni Specific examples of the "lower alkoxy group" include benzyloxy, phenethyloxy and the like.

Examples of the salt of the compound of the present invention represented by the formula [I] include an acid addition salt, and particularly preferably a physiologically acceptable acid addition salt. Specific examples of the acid addition salt include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and oxalic acid, maleic acid, fumaric acid, lactic acid, lingo and the like. Examples thereof include salts with organic acids such as acid, cunic acid, tartaric acid, benzoic acid, and methanesulfonic acid. In the compounds of the present invention, those having a carboxyl group in the definition of the substituent or R ₂ also exist as an alkali metal salt or a salt with an organic base. Examples of such salts include salts with alkali metals such as sodium and potassium, and salts with organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine and dicyclohexylamine. No.

 These acid addition salts, alkali metal salts or salts with organic bases may exist in the form of hydrates or solvates, and these are also included in the compounds of the present invention.

The compound of the present invention represented by the formula [I] has two asymmetric carbons. Carbon atoms in ie formula (II) are carbon atoms, and R ₅ arsenide Dorokishiru group is attached are attached is non Hitoshisumi crowd. Therefore, four stereoisomers may exist in the compound of the present invention. These optically active substances, racemates and mixtures thereof are also included in the compounds of the present invention.

Among the compounds of the present invention, preferred are compounds represented by the following general formula (I-a) wherein the substituent W is bonded to the 3-position of the indole ring.

Wherein R, R ₂ , R ₃ , R ₄ and R ₅ are the same as above.

And a salt thereof. Among them, in the formula [I-a], the compound is bonded to the indole ring at the 5, 6 or 7-position and R ₂ is a hydrogen atom, or a salt thereof, or in the formula [I-a], R ₂ Is a group other than a hydrogen atom, and one of Ri and R ₂ is bonded to the 6-position of the indole ring and the other is bonded to the 7-position, and a salt thereof is more preferable. Further preferred compounds are a lower alkyl group in which R is substituted with a hydroxy group, a fuunylsulfonylamino group, a lower alkylsulfonylamino group, a di-lower alkylaminosulfonyl group in the general formula [I-a]. Group, or (a) ヽ (bl), (c-1) and (d) below

 (a) group represented by the formula X-Ra

 (Where X and Ra are the same as above)

 Rb— 1

 I

(b-1) Group represented by the formula [0 (CH ₂ ) it—CH] n—Rbb

 (Where Rb-1 is a hydrogen atom or a lower alkyl group, and Rbb, m and n are the same as described above)

(c- 1) formula one 0 (CH ₂₎ a group represented by the p-RC- 1

 (Where Rc-1 is a lower alkanoyl group, a phenyl group or a mono-lower alkylaminocarbonyl group, and p is the same as above)

(d) a group represented by the formula: Y— (CH ₂ ) q—Rd

(Where Y, Rd and q are the same as above) Wherein R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a hydroxy group, a hydroxy group, a lower alkoxy group, or the above (b-1) or (c Indole derivatives and salts thereof which are the same groups as in 1). Among them, in the formula [I-a], represents a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group, a phenyl lower alkoxy group or a di-lower alkyl group. a Minosuruhoniru group, R ₂ is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower grade alkoxycarbonyl group, a lower alkoxycarbonyl lower alkoxy group, carboxy lower alkoxy group or Fuweniru lower alkoxy group, R ₃ Is a hydrogen atom, R ₄ or a logen atom, and R ₅ is a methyl group. Indole derivatives and salts thereof are more preferred.

Particularly preferred compounds are those represented by the formula (I-a), wherein is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a methyl group, a methoxycarbonyl group, a methoxycarbonylmethoxy group, a carboxymethoxy group, An indole derivative having a benzyloxy group or a dimethylaminosulfonyl group, R ₂ being a hydrogen atom or a methoxy group, R ₃ being a hydrogen atom, R ₄ being a chlorine atom, and R ₅ being a methyl group; And its salts.

The most preferred compound is a methoxy group, an ethoxy group, a methoxycarbonyl group, a methoxycarbonylmethoxy group or a methoxy group in which R, is bonded to the 6-position or the 7-position of the indole ring in the general formula [I_a]. An indole derivative having a carboxymethoxine group, R ₂ and R ₃ being hydrogen atoms, R ₄ being a chlorine atom, and R ₅ being a methyl group, and salts thereof.

 Specific examples of the most preferred compounds include

① 2— [3— (7-Methoxyindole-1-inole) -2-propylamido [No] 1-11 (3-chlorophenyl) ethanol

 ② 2- [3- (7-Ethkinindole-l-inole) -l-propylamino] -l- (3-chlorophenyl) ethanol

 ③ 2- [3- (7-Methoxycarbonylmethoxyindole-3-yl) -1-2-propylamino] 1-1- (3-chlorophenyl) ethanol

 ④ 2- [3- (7-Carboxymethoxyindole-1-3-inole) -1 2-Pupylpyramino] -11- (3-chlorophenyl) ethanol

And optical isomers and salts thereof.

Specific examples of the compounds included in the present invention include the compounds in Tables 2, 3 and 4 below, and salts thereof.

λ i960Λ,

CM

CO

Table 4

 CI

 *: The substituent is bonded to the 6- or 7-position of the indole ring.

 The compound of the present invention can be produced by the method described below, production method (a):

 The compound of the present invention represented by the formula (I) has the following formula (III)

Wherein R ₄ is the same as above.

The compound represented by the following formula (IV)

Wherein R, R ₂ , R ₃ and R ₅ are the same as above.

Or a salt thereof. This reaction is carried out in a suitable solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like.For example, alcohols such as methanol, ethanol, isopropyl alcohol, ketones such as acetone, methylethylketone, methylene chloride, and chloroform Halogenated hydrocarbons such as acetyl ether, tetrahydrofuran, ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, N-N-dimethylformamide, dimethyl These solvents are used alone or in combination of two or more. When compound (IV) is in the form of an acid salt such as an inorganic acid salt such as hydrochloride or hydrobromide and an organic acid salt such as oxalate, maleate or fumarate. This reaction is carried out in the presence of a base. Specific examples of the base include sodium bicarbonate, alkali bicarbonate such as potassium bicarbonate, sodium carbonate, aluminum carbonate such as potassium carbonate, or triethylamine, tributylamine, diisopropylethylamine, Organic bases such as N-methylmorpholine are exemplified. When the substituent R or R ₂ contains a carboxyl group, the reaction is carried out in the presence of a base as described above.

 The reaction temperature varies depending on the type of the starting compound used and the like, but is usually from room temperature to about 150, preferably from about 25 ° C to about 100 ° C.

 In the present production method, both the compound [III] and the compound [IV] as the raw material compounds have an asymmetric carbon, and the configuration of the asymmetric carbon is the same as that of the product of the compound of the formula [I]. Is held. That is, for example, a compound of the formula [II] which is an R-form and a compound of the formula [IV] which is an R-form can yield the compound of the present invention having a (R.R) configuration.

The optically active form of the compound of the formula [III] can be produced, for example, by the method of Bloom, JD et al. [J. Med. Chem., 35, 3081-3084 (1992)] or Eliel, EL and the method of Delmonte. DW !: J. Org. Chem..2_, 596—597 (1956)]. The optically active form of the compound of the formula [IV] can be produced, for example, according to the method of Repke, DB and Ferguson, WJ [J. Heterocycl. Cheni., 13, 775-778 (1976)].

 The starting compound represented by the formula [IV] can be produced, for example, according to the method described in J. Org. Chem., 25, 1548-1558 (1960). Further, among the starting compounds of the above formula [IV],

H ₂ N-CH-CH ₂ —

R ₅

(Wherein, R ₅ is the same as described above)

Can be produced according to the method described in J. Org. Chem., 5, 4, 2944-2295 (1986).

Production method (b):

 Among the compounds of the present invention, a compound in which the substituent R in the formula (I) is a more limited group ', that is, a compound represented by the following formula [I-b]

Wherein R is a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or (A) ', (b), (c) Or a group selected from (d) ′ or may form a methylenedioxy group together with R ₂ , and the methylenedioxy group may be substituted with a carboxyl group or a lower alkoxycarbonyl group.

 (a) 'Formula X'—group represented by Ra

 (Where X 'is 0 or S, and Ra is the same as described above. However, when X' is S, Ra is a lower alkyl group.)

 Rb

 I

(b) a group represented by the formula — [0 (CH ₂ ) m—CH] n—Rbb

(Where Rb, Rbb, m and n are the same as above)

(c) a group represented by formula 1 0 (CH ₂ ) p—Rc

(Where Rc and p are the same as above)

(d) 'Formula I Y' — (CH ₂ ) q—group represented by Rd

(Where Y 'is S and Rd and q are the same as above)

R ₂ , R ₃ , R ₄ and R ₅ are the same as described above)

The compound represented by the following formula (V)

R 4

 <cH-CH-one NH [V]

 OH

(Where R ₄ is the same as above)

The compound represented by the following formula (VI)

〔式中、 R 、 R ₂、 R ₃および R ₅は前記と同じ〕

(Wherein, R, R ₂ , R ₃ and R ₅ are the same as described above)

Can be produced by reacting with a compound represented by the formula under reducing conditions.

 The term "reacting under reducing conditions" in the present process refers to the reaction in the presence of a reducing agent or a catalytic reduction catalyst capable of reducing only the imine moiety formed during the reaction without affecting the carbonyl group. This means reacting the compound of the formula [V] with the compound of the formula [VI].

 Examples of the reducing agent used here include sodium cyanoborohydride, and examples of the catalytic reduction catalyst include palladium and platinum oxide.

 This reaction is performed in a suitable solvent in the presence of a reducing agent or a catalytic reduction catalyst. As the solvent, alcohols such as methanol and ethanol are preferable. The reaction temperature is usually selected from the range of about 20 to about 80 ° C. when using the reducing agent, and is usually in the range of about 10 to about 25 ° C. when using the catalytic reduction catalyst. .

Production method (c):

In the above formula (I), a compound having no carbonyl group or cyano group in the substituent R or R ₂ , that is, the following formula (I-c)

[In the formula, "represents a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or the following ( a) or (c) " And may form a methylenedioxy group together with R ₂ ″.

 (a) group represented by the formula X-Ra

(Where X and Ra are the same as above)

(c) a group represented by “formula 0 (CH ₂ ) p—Rc”

 (Where Rc "is a hydroxyl group, a phenyl group, or a compound represented by the following formula:

 0

 II

P-OR _A

 OR A

(Where R is a hydrogen atom or a lower alkyl group), and p is the same as above.

R ₂ "represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a hydroxy group, a hydroxy group, a lower alkoxy group, or a group represented by the above (c)"; Together with "" may form a methylenedioxy group.

R ₃ , R ₄ and R ₅ are the same as above)

The compound represented by the following formula [V I I]

_{Wherein, Ri "R 2", R} 3, R 4 and R ₅ are as defined above]

Can be produced by passing the compound represented by the formula

This process is carried out in a solvent in the presence of a reducing agent. Examples of the bulking agent that can be used here include diborane, lithium aluminum hydride and the like. Examples include an alkoxy complex or a transition metal salt, aluminum chloride, boron trifluoride, phosphorus oxychloride, or sodium borohydride to which a carboxylic acid (for example, acetic acid or trifluoroacetic acid) is added. Examples of the solvent include ethers such as getyl ether, tetrahydrofuran, dimethoxetane, dioxane, and diglyme. The reaction temperature varies depending on the type of the reducing agent and the like, but is usually about 0 ° C to about 160 ° C.

In this production method, the configuration of the asymmetric carbon of the starting compound [VII] is retained in the product _c

 The raw material compound [V I I] is a novel substance, for example, the following formula [I X]

Wherein R ₄ is the same as above.

The compound represented by the following formula (X)

[X]

 R,

(Wherein, R, R ₂ ", R ₃ and R ₅ are the same as described above)

Or a salt thereof.

The reaction between the compound [IX] and the compound [X] is carried out by N, N'-dicyclohexylcar positimide, 1-ethyl-3- (3-dimethylaminobutyryl) carbodiimide hydrochloride, N, N ' —Carbonidimidazole, N, N'—carbonyldi The reaction can be carried out in the presence of a condensing agent such as succinic acid imid, 11-ethokin-2-yl-2-ethoxin-1,2-dihydroquinoline, diphenylphosphoryl azide and propanephosphonic anhydride. When using N.N'-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminobutyral) porposimid hydrochloride as the condensing agent, N-hydroxysuccinic imidate, 1-hydroxyl The reaction may be carried out by adding benzotriazole or the like.

This reaction is carried out in an appropriate solvent ₌ Examples of the solvent include the solvents described in the production method (a). The compound [X] can be used in the form of an acid addition salt as described in the production method (a). In this case, the reaction is carried out using triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine. It is performed in the presence of an organic base such as The reaction temperature is usually about 20 ° C to about 50 ° C.

 The configuration of the compound [IX] and the asymmetric carbon in the compound [X] are retained in the product (compound [VI1]).

 The optically active form of the compound [IX] can be obtained, for example, by the method of Collet A. and Jacques, J. [Bull. Soc. Chim. France, 3 3 3 0—3 3 3 4 (1 9 7 3 )]].

 The optically active form of the compound of the formula [X] can be produced, for example, according to the method described in Japanese Patent Laid-Open Publication No. 63-22559.

 The product obtained by any of the above methods can be isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation.

The product obtained in any of the production methods takes the form of an acid addition salt or a free base depending on the reaction conditions. These products can be converted into the desired acid addition salts or free bases by conventional methods. In any of the above-mentioned production methods, the substituent or R ₂ is an amino group or the following formula:

0

 II

 —— P-OH

When it is a lower alkoxy group substituted by a group represented by OH, or when a substituent R or R ₂ contains a carbonyl group or a hydroxyl group, the substituent is previously substituted with a commonly used protecting group. After performing the reaction in a protected state, the desired target compound can be efficiently produced by removing the protecting group.

 When the compound of the present invention or the starting compound obtained by each of the above-mentioned production methods is a racemate or a diastereomer mixture, a conventional method, for example, according to the method described in European Patent Application Publication No. It can be separated into each stereoisomer.

BEST MODE FOR CARRYING OUT THE INVENTION

Pharmacological test

 The following pharmacological tests were performed to determine the representative compounds of the present invention.

① human; S ₃ and yS ₂ adrenergic receptor stimulating action,

 ② hypoglycemic action, and

 ③ Anti-obesity effect

Was evaluated.

First, it describes human / 3 ₃ and ₂ Adorenarin receptor preparation how highly expressing cell lines, then test examples are shown using them.

Process for the preparation of human ₃ highly expressing cell lines § Dorenarin receptor eleven

(1) Preparation of expression vector: 11 Expression vector pKCRH2 for animal cells [Mishina et al., Nature 307: 604-608 (1984)] was digested with restriction enzyme Sal I and made blunt-ended with DNA Blunting Kit (Takara Shuzo). Next, another expression vector pSV2-neo for animal cells [Southern and Berg, J. Mol. Appl. Genet. 1: 327-341 (1982)] was ligated with restriction enzyme 8 (:(; {Digested with 1 I and made blunt ends with DNA Blunting Kit. These were ligated using DNA Ligation Kit (Takara Shuzo), introduced into Escherichia coli HB101 by a conventional method, and transformants were selected. -Plasmid DNA is extracted from this transformant, digested with the restriction enzyme Pstl, and clones that obtain fragments of about 3.8 kbp, 2.2 kbp, 1.4 kbp, and 0.9 kbp are selected, and pKCNO and This plasmid pKCN0 was digested with the restriction enzyme Hindi II and ligated with the following synthetic adapter 1 (SEQ ID NO: 1) using a DNA Ligation Kit.

 5 '-AGCTCCTGCAGGCGCGCCGATATCTCGAGCGGCCGCGGTACCA-3'

 3′-GGACGTCCGCGCGGCTATAGAGCTCGCCGGCGCCATGGTTCGA-5 ′ This was introduced into Escherichia coli HB101 by a conventional method, and plasmid DNA was extracted from the selected transformant. After digestion of this plasmid DNA with restriction enzymes DraI and HindiII, a clone from which a fragment of about 430 bp was obtained was selected, and this plasmid DNA was used as an expression vector pKCN1.

(2) Preparation of expression plasmid: 11

RNA was extracted from human neuroblastoma SK—N—MC (ATC C HTB10) by a conventional method, and cDNA was synthesized using Superscript Systems (Life Technologies). This cDNA was amplified using the following oligonucleotides 1 (SEQ ID NO: 2) and 2 (SEQ ID NO: 3) as primers using a GeneAmp PCR Kit (Perkin-Elmer). When performing the PCR reaction, 10% dimethyl sulfokind was added to the reaction solution. δ'-CCACCTGCAGGTGATTTGGGAGACCCC-3 '——Ori: Πnucleotide' 15′-TTCTCGAGCCGGGGAATCCCATGGGAC-3 '—— Oligonucleotide' 2 The fragment was isolated. This fragment was ligated with the expression vector pKCN1 digested with the restriction enzymes Sse8387I and EcoRV, introduced into E. coli HB101 by a conventional method, and plasmid DNA was extracted from the selected transformant. As a result of examining the nucleotide sequence of a fragment of about 1.3 kbp obtained by digesting this plasmid DNA with restriction enzymes Sse83871 and Xhol, this sequence was reported by Lelias et al. [FEBS Lett. 324: 127-130 (1994)]. The sequence was identical to that of the human _3- adrenergic receptor cDNA. The plasmid for expression of the human _3- adrenergic receptor was designated as pKREX10. (3) Preparation of highly expressing cell line: 11

The human _3- adrenergic receptor-expressing plasmid pKREX10 was introduced into Chinese hamster ovary cells CHO—K1 (ATC CCL61) by the calcium phosphate method, and the transformants were transformed into 60 Oi / gZml of G—418 (Life- Technologies) containing MEM—Dulbecco medium (ICN Biooraedicals). The medium was supplemented with 10% fetal calf serum and 11. S / igZnil proline. After removing the medium from the 69 G-418 resistant clones, the cells were removed by standing at 37 ° C. for 10 minutes in phosphate buffered saline containing 0.5 mM ethylenediaminetetraacetic acid (EDTA). The cells were collected by centrifugation, and suspended in 10 mM Tris-HCl buffer (pH 7.5) containing lmM EDTA to about 510 ⁶ cells / ml. The suspension 20/1 1. 5nM (-) 3 - [ 125 I] iodocyanopindolol (Amersham) 1% © shea serum albumin, including the 0.1% NaN ₃ and 2 Omm HEPES buffer (pH 7.4) Mix in RPMI-1640 medium (ICN Biomedicals) 20 The mixture was allowed to stand at 4 ° C for 2 hours. Using a bio-dot device (Bio-Rad Laboratories), the filter was overwashed with a glass filter GF / C (Whatman) pre-soaked in 0.3% polyethyleneimine, and the radioactivity on the filter was measured using an alpha-ray meter. Measured. The clone with the highest radioactivity was selected and designated as a cell line highly expressing human 3-adrenergic receptor CHOZpKREX 10-36.

To 0

 Method for preparing a cell line highly expressing human 2 adrenergic receptor: 11

CDNA was synthesized from human brain-derived Poly (A) ⁺ RNA (Clontech: product number: CL 6516-1) using Superscript Systems (Life Technologies). This cDNA was amplified by GeneAmp PCR Kit CPerkin-Elmer using oligonucleotides 3 (SEQ ID NO: 4) and 4 (SEQ ID NO: 5) shown below as primers.

5'-ACACCTGCAGGTGAGGCTTCCAGGCGTCC-3 '——Oligonucleotide' 3 5'-TGTAAGCTTCTGCTTTACAGCAGTGAGTC-3 '—— Oligonucleotide'4 Was isolated. This fragment was combined with an expression vector pKCN1 digested with restriction enzymes Sse8387I and HindiII, introduced into Escherichia coli HB101 by a conventional method, and plasmid DNA was extracted from the selected transformant. The nucleotide sequence of a fragment of about 1.4 kbp obtained by digesting this plasmid DNA with restriction enzymes Sse8387 I and Hindi II was examined. As a result, this sequence was found to be Kobilka. BK et al. [Proc. Natl. Acad. Sci. USA , 8. 1.46-50 (1987)] and the sequence of the human ^ :! adrenaline receptor cDNA. The human y9 ₂ adrenergic receptor expression bra corner de and PKREX21, in the same manner as the human ^ S ₃ adrenoceptor highly expressing cell line was introduced into CHO- K1 cells, human ^ ² Adorenari Cell line CH0ZPKREX21-8 was obtained.

Test Example 1 Stimulation of human / 5 adrenergic receptor: 11

Human; S ₃ Adorenarin receptors highly expressing cell line CHOZpKREX 10- 36 10% © shea calf serum, 11.5 / proline IgZml, and 200 including ng ZML of G-418 were cultured MEM- Dulbecco medium at 3 days After removing the medium, the cells were removed by standing at 37 ° C for 10 minutes in a phosphate buffered saline containing 0.5 mM EDTA. Collect the CHOZp KREX10-36 cells by centrifugation and place them in a Hanks' balanced salt solution (ICN Biomedicals) containing lmM ascorbic acid and ImM 3-isobutyl-1-methylxanthine to about 2 x 10 ⁶ cells Zml. Suspended. The suspension 100 / il and the test compound were mixed in the same balanced salt solution 500 / il, reacted at 37 ° C for 30 minutes, and then stopped by boiling for 5 minutes. After centrifuging the reaction solution, the amount of cyclic AMP in the supernatant was measured using cAMP EIAS system (Amersham).

Further, instead of the highly expressing cell line CHOZpKREX 10- 36 of human S ₃ Adorenarin receptors, by the same operation using a highly expressing cell line C HO / pKREX21 one 8 of human Adorenarin receptor, cyclin click The amount of AMP was measured.

10- ⁵ M (-) 100% upon the addition of an isoproterenol or without addition when Saikuri' click AMP amounts, respectively, to 0%, the relative% maximum cycle click AMP accumulation effect of the present compounds [ I. A. (%)).

In addition, the concentration (EC ₅₀ ) that caused 50% cyclic AMP accumulation was calculated from the concentration-response curve of each compound by the least squares method.

Table 5 shows the test results. Compounds A. B and C listed at the beginning were used as comparative control compounds. Table 5

Ne ^1: compound of Example 1 (hereinafter the same).

* ² : Measurement is impossible because the action is extremely weak. * ³ : (1)-Isoproterenol The EC ₅₀ values are low and IA value is higher compounds, human 5 ₃ or / 5 ₂ § de Renarin receptor stimulating action is evaluated as strong. Accordingly, as shown in Table 5, the compound of the present invention, in particular Example 1, 1 one A, 1 one A- b, 2, compounds of the 2-A and 1 4 for human / 5 ₃ Adorenarin receptor It can be seen that it has a strong stimulating effect. Also, human ₃ A Dorenari emissions receptor stimulating action of the compound of the present invention Ru der clearly stronger than the human beta ₂ Ryo Dorenarin receptor stimulating effect. In particular, Example 1, 1-Alpha, 1 one alpha-b, 2, compounds of the 2-A and 14 have excellent selectivity for human S ₃ Adorenarin receptor _c

_{On the other} hand, the human ^ ₃ adrenergic receptor-stimulating effect of the comparative compounds A. B and C described at the beginning of the present specification is considerably weaker than the compound of the present invention.

 In addition, the compound of the present invention is used as a human! Examination of the adrenergic receptor stimulating effect showed that the effect was hardly recognized.

From the above results, the present compound can be said to be human 3 ₃ Adorenarin receptor stimulants with excellent selectivity.

Test example 2 Fasting mice hypoglycemic effect: 11

The test compound suspended in a 0.5% tragacanth solution was orally administered to fasted ddY male mice (20 to 30 g), and blood was collected before administration and 3 hours after administration. (Hexokinase ZG 6 PDH i¾) [Bergmeyer, H.U. (eds.), Methods in Enzymology, Vol. VI, 3rd Edition, Verlag Chemie GmbH, Weinheim Deerfield B each, Florida Basel 163-172 (1984)]. The hypoglycemic action of the test compound was expressed using the dose (ED ₂₅ ) that reduced the blood glucose level by 25% before administration of the compound as an index. As a control compound, Gliclazide, a commercially available drug for treating diabetes, was used. Table 6 shows the results. Table 6

 *: Compound of Example 1 (the same applies hereinafter).

Test Example 3 Anti-obesity effect of obese diabetic mice: 11

 The test compound suspended in a 0.5% tragent solution was orally administered to an obese diabetic mouse (KK-AyZTa J cl. Female; 50 to 60 g: CLEA Japan) at a dose of SmgZkg Z for 3 weeks. After a week, the retroperitoneal adipose tissue and interscapular adipose tissue were excised, and their weight was measured as white adipose tissue and brown adipose tissue, respectively. Table 7 shows the results.

 *: There is a significant difference from the control at P <0.01.

All the compounds of the present invention have low toxicity. For example, in an acute toxicity test using mice, the compound of Example 11A showed no toxicity at an oral dose of 30 OmgZkg (body weight). Therefore, there is no problem in the safety of the compound of the present invention for a living body in consideration of the efficacious dose. The compound of the present invention is a highly selective _3- adrenergic receptor stimulant, and is useful as an agent for preventing and treating obesity and diabetes in mammals including humans. In addition, for the treatment of irritable bowel syndrome, acute or chronic diarrhea, and improvement of symptoms such as abdominal pain, nausea, vomiting, and upper abdominal discomfort associated with peptic ulcer, acute or 胃 gastritis, biliary dyskinesia, cholecystitis, etc. Again, the compounds of the present invention can be used.

 When the compound of the present invention represented by the formula [I] and a physiologically acceptable salt thereof are used as a βζ7-drenergic receptor stimulant, the administration route is oral administration, non-peripheral administration, or intrarectal administration. Administration may be any, but oral administration is preferred. The dose varies depending on the administration method, the patient's symptoms and age, the type of treatment (prevention or treatment), etc., but is usually 0.01 to 2 OmgZkgZ days, preferably 0.05 to 1 OmgZkgZ days. It is.

The compound of the present invention is usually administered in the form of a preparation (pharmaceutical composition) prepared by mixing with a pharmaceutically acceptable carrier for preparation. As the carrier for the preparation, a substance which is commonly used in the field of the preparation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxybutyrate Pill starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, low-substituted hydroxypropylcellulose, hydroxypropyl pillmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light maleic anhydride, Magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerine Le, purification Rano Li down, glycerin opening Examples include gelatin, polysorbate, macrogol, vegetable oil, wax, nonionic surfactant, propylene glycol, water and the like.

 Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections, and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of injectables, it is advantageous to prepare a solution by adding a physiologically acceptable acid addition salt of the compound represented by the formula [I] to water. , A pH adjuster, a buffer and a preservative may be added.

 These preparations may contain the compounds of the invention in a proportion of at least 0.01%, preferably 0.05 to 70%. These formulations may also contain other therapeutically effective ingredients.

Example

 Hereinafter, the present invention will be described specifically with reference to Reference Examples and Examples, but the present invention is not limited to these Examples and the like.

 The compounds were identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum, and the like.

 In the following, the following abbreviations may be used to simplify the description in this specification.

 Me: methyl

 E t: ethyl

 P h: Funil

 E: Ethanol

M: methanol H: n-hexane

 DE getyl ether

 C F Black mouth Honolem

 E A Ethyl acetate

 DMF dimethylformamide

 s: single line

 d: Double line

 dt: double triplet

 dd: Double double line

 t: Triple line

 m: Multiple line

 Q: Quadruple

 MS: Mass Spectrum

Reference Example 11

 Production of 3- (2-aminobutyryl) -17-methindindole: The compound of the title reference example can be produced according to the method described in British Patent No. 974, 893 by the following method.

(1) 16 ml of dimethylformamide (that is, DMF) is cooled in an ice bath, 5 ml of phosphorus oxychloride is added dropwise, and the mixture is stirred for 10 minutes. According to the method described in Heterocycles, 16, 1119-1-1124 (1981), 16 g of a DMF solution of 6.5 g of 7-methoxine-donoré synthesized from 3-methyl-2-nitroisole was added dropwise at room temperature. Stir for 2 hours. Add 30 ml of a 30% aqueous sodium hydroxide solution under ice-cooling, heat in a hot water bath at about 80 ° C for 5 minutes, and allow to cool. The precipitate is removed, washed with water, and dried to obtain 4.6 g of crude 7-methoxyindole-13-aldehyde. (2) A mixture consisting of 3.6 g of ammonium acetate, 1 ml of acetic anhydride and 3.2 ml of acetic acid is heated and stirred at 50 ° C. for 20 minutes. The temperature is raised to 100 ° C, 2.25 g of sodium acetate is added, and 3.2 ml of acetic anhydride is slowly added dropwise. After allowing to cool, the precipitated solid is added by adding water, and the precipitated solid is collected, washed with water, and dried to obtain 3.35 g of crude 1- (7-methoxyindole-13-yl) -12-nitropropene.

 (3) A solution of 60 ml of a tetrahydrofuran solution containing 3.2 g of the above-mentioned ditropropene compound is dropped into 6 g of a dimethyl ether ether suspension of 3.2 g of lithium aluminum hydride under ice-cooling, and the mixture is heated under reflux for 5.5 hours. Under ice-cooling, a saturated aqueous solution of potassium sodium tartrate was added dropwise to the reaction solution, and the insoluble material was removed by filtration. The filtrate was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 3.2 g of the desired product (oil) as a crude product. This target product is used as a starting compound in Example 1 described later.

MS (m / z): 205 (MH ⁺ )

Reference Example 2-

 Preparation of 3- (2-aminobutyral pill) -1 6-methoxycarbonyl methindole

 (1) Add 2.9 g of 6-hydroxydionone, 2.7 g of methyl acetate, 5.5 g of potassium carbonate and 0.2 g of potassium iodide to 1 OOral of acetone, and heat to reflux for 8 hours. After cooling the reaction solution to room temperature, insolubles are removed and the solution is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with chloroform to give 2.83 g of 6-methoxycarbonylmethoxyindole.

iH—NMR spectrum (CDC) ₃ : 3.78 (3H, s, COOCH ₃ ). 4. 67 (2H.s.OCH ₂ ), 6.49 (1 Hm), 6.83 (1 H.ID), 6.88 (1 H.s), 7.11 (1 H, m) .7.53 (1 H, B), 8.2 ( 1 H, s, NH)

 (2) To 5 Oml of a benzene solution containing 2.77 g of the above product, 17.8 ml of a benzene solution containing 3.56 g of 2-ditroproben is added, and the mixture is heated under reflux for 15 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform to give 3- (2-nitropropyl) -16-methoxycarbonylmethoxyindole (oil) 2.15 get g.

- NMR spectrum _{(CDC 1 3): 1.56 (} 3H, d, J = 7Hz, CH CH 3), 3.10-3.48 (2H.m, CH 2 CHN0 2) .3.77 (3 Hs CO OCH 3), 4.64 ( _{2H, s, OCH 2),} 4.92 (1 H, m, CHN0 2) .6.76 ~7.05 (3H, n), 7.48 (1 Η, πι), 8.08 (1 H, s, NH)

 (3) The above product 2. Dissolve lg in 50 ml of ethanol, add Raney-Niggel, and conduct normal pressure passage at 50 ° C. After the theoretical amount of hydrogen has been absorbed, the Raney Nigel is removed and the effluent is distilled off under reduced pressure to give crude 3- (2-aminoprovir) —

1.98 g of 6-methoxycarbonylmethoxyindole (oil) is obtained. This compound is used as a starting compound in Example 7 described later.

MS (m / z): 263 (MH ⁺ )

Reference Examples 3 to 13 1- By performing the same reaction and treatment as in Reference Example 1 or 2, the starting compounds shown in Table 8 below are obtained. Table 8

 : Synthesized by the same production method as in Reference Example 1.

* ² : Synthesized by the same production method as in Reference Example 2.

Example 1:-

 2- [3- (7-Methoxyindole-3-inole) -1-propylamino] 1-1 Production of 1- (3-chlorophenyl) ethanol: 1

Manufacturing method (a): One

To 2 O ml of methanol, 0.77 g of (3-chlorophenyl) oxylan and Add 2.16 g of 3- (2-aminobutyral pill) -17-methoxyindole and stir at room temperature for 64 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with chloroform-formumethanol (12: 1). The fraction containing the desired product was reduced in vacuo to give 1.06 g of an oil. obtain.

'H-NMR spectrum _{(CDC 1 3):. 1.12} (. 3H.d J = 7Hz, CH CH 3) 2.61 (lH.m), 2. 78~2.86 (2H.IB), 2.88~3.12 (2 Hm), 3.95 (3 Hs, OCH ₃ ), 4.56 (1 H, m, CHOH), 6.65 (1 H, m), 6.93 to 7.09 (2H, ra), 7.11 to 7.29 (4 H, m), 7.33 (1 H, m), 8.25 (1 Hs, indole NH)

 Further, by treating 0.3 g of this oily substance with fumaric acid, 0.15 g of the fumarate of the target product is obtained (fumarate of the compound of Example 1).

 Melting point 143-147 ° C (recrystallized from ethanol-ethyl ether) Production method (b): 1

 0.4 g of 7-methoxyindole-1-acetone and 0.45 g of 2- (3-chlorophenyl) ethanolamine hydrochloride synthesized according to the method described in British Patent No. 974.893 were added to 10 ml of methanol, and cooled with ice. Then, 0.2 g of sodium cyanoborohydride is added and stirred for 5 minutes, and then stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography, and eluted with chloroform-methanol (15: 1) to obtain 0.58 g of the desired product (oil).

Manufacturing method (c): One

(1) Benzotritriene was added to 80 ml of DMF solution containing 12.24 g of 3- (2-aminopropyl) -17-methoxyindole and 7.46 g of 3-chloromandelic acid. After addition of 17.68 g of azole-N-oxytris (dimethylamino) phosphoniumhexafluo phosphite, add 9.8 ml of triethylamine. After stirring at room temperature for 5 hours, add ethyl acetate to the reaction mixture, wash with water, 10% aqueous solution of citric acid, water, saturated aqueous sodium hydrogen carbonate, water, and saturated saline in that order, and dry over anhydrous magnesium sulfate. . After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate Zn-hexane (1: 1 → 2: 1) to obtain N- [3- (7-methinequinine). There are obtained 14.0 2 g of dol-3-yl) -2-propyl] -13-chloromandelic acid amide (oil).

- NMR spectrum _{(CDC 1 3): 1.12,} 1.18 (3 H, d, J = 7 Hz, CHCH 3), 2.82 ~ 2.95 (2H, m, CH 2 CH), 3.97 (3H, s, OCH ₃ ), 4.33 (1Η, πι, CHCH ₃ ), 4.85 (1 H, s, CHOH), 6.65 (1 Hm), 6.86 to 7.37 (7H, m), 8.26 (1 H, d, J = 13 (Hz, C ONH)

 (2) 144 ml of a tetrahydrofuran solution containing 13.4 g of the above amide compound is added dropwise to 144 ml of a 1 M borane-tetrahydrofuran complex solution at 20 ° C. After heating under reflux for 4 hours, 15 Oinl of methanol is added dropwise under ice cooling. . After refluxing for 1 hour to decompose excess borane, the solvent is distilled off under reduced pressure. To the residue is added chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography and eluted with chloroform-formumethanol (20: 1 → 10: 1) to obtain 7.35 g of the desired product (oil).

Example 11 A:-

2- [3- (7-Methoxyindole-1-yl) -2-propylamino] 1- (1R)-Production of 1- (3-chlorophenyl) ethanol:- (R)-(3-chlorophenyl) oxylan (SE PRACOR, optical purity: 99.2% ee) was used instead of (3-chlorophenyl) oxysilane in Example 1, and the production method of Example 1 was used. The desired product (oil) is obtained by reaction and treatment in the same manner as in (a).

MS (mZz): 359 (MH ⁺ )

Example 11 A—a and b: ——

2-[(21¾ or 23) -3- (7-Methoxyindole-1-inole) -1- 2-propylamino]-(1R) -1-1 (3-chlorophenyl) ethanol and 2-[(2S Or 2 R) —3- (7-Methoxy-indol-3-yl) —2-propylamino]-(1R) —11- (3-chlorophenyl) ethanol

 Example 11 2- [3- (7-Methoxyindole-13-yl) -1-2-propylamino] -1 (1R) -1 (3) which is a mixture of two diastereomers obtained in 1A Separation of 3.Og of chloro (phenyl) ethanol using column chromatography, 0.82 g of the compound eluting in the less polar part (11A-a) and the compound (11 You can get 1.12g of A-b).

Compound (1-1 A—a):

 Retention time in high performance liquid chromatography (HPLC): 20.3 minutes (optical purity:> 99% d.e.)

 HPLC separation conditions:

1. Column: CH I RALPAK AD (4.6ram0x25Omra _: Daicel Chemical Industries)

2. Mobile phase: n-hexane // ethanol Jethylamine = 85Z15 0.1 3.Flow rate: 0.4mlZ min

 4. Temperature: 40 ° C

 5. Detection wavelength: 254nm

 Melting point: 129-130 ° C (recrystallized from ethyl acetate-n-hexane)

— NMR spectrum (CDC ₃ ): 1.12 (3H, t, J = 7 Hz, CH CH ₃ ), 2.57 (lH, dd, J = 12, 7 Hz), 2.81 (2H, d, J = 7 Hz _{( CH 2 CH) .2.91~3.09 (2H,} m), 3.95 (3H, s, 〇_CH _{3), 4.5 9 (1 H} , dd, J = 8, 4 Hz, CHOH), 6.64 (1 Hd, J = 8 Hz), 6.95 (1 Hd, J = 2 Hz), 7.03 (1 Ht, J = 8 Hz), 7.10 to 7.24 (4 Hm), 7.32 (1 H, m), 8.25 (1 Hs, indole NH)

Compound (1-1 A—b):

 Retention time on HP LC: 24.5 min (optical purity:> 99% de.e.) HPLC separation conditions: 1 Same as separation conditions for compound A-a.

 Melting point: 86-87 ° C (recrystallized from ethyl acetate-n-hexane)

'H- NMR spectrum _{(CDC1 3):. 1.12 (} 3 H, d, J = 7Hz, CHC H 3) .2.62 (1 H.dd, J = 12.9 Hz), 2.82 (2H, d J = 7Hz, CH ₂ CH), 2.87 (1 H.dd, J = 12, 4 Hz) .3.05 (lH.m, CHCH ₃ ). 3.96 (3H.s, OCH ₃ ). 4.49 (1 H.dd.J = 9.4Hz, CHOH) .6.6 odH.d, J = 8 Hz) .6.99 (1 Hd, J = 2 Hz), 7.04 (lH, t.J = 8 Hz), 7.12 to 7.25 (4H'm ), 7.33 (lH.m), 8.26 (lH, s.indole NH)

Example 2: One

 Production of 2- [3- (7-ethynindole-1-yl) -2-propylamino] 1-1- (3-chlorophenyl) ethanol:

0.93 g of (3-chlorophenyl) oxylan and 3- (2-aminoprovir) The reaction and treatment were carried out in the same manner as in Production Method (a) of Example 1 using 2.18 g of 1-7-ethokinindole to obtain 1.16 g of the desired product (oil).

'.Eta. NMR spectrum _{(CDC 1 3): 1.12 (} 3H, d, J = 6Hz, CH CH 3), 1.48 (. 3H.t J = 7Hz, CH 2 CH 3) .2.4 (2H, br , NH, 0 H), 2.60 (1 Hdt, J = 12.8 Hz), 2.77 to 2.96 (3 H.m) .3.04 (1 Hm), 4.20 (2H, q, J = 7 Hz.CH ₂ CH ₃ ), 4.δ5 (1 H.dd, J = 9, 4 Hz, CHOH), 6.63 (lH, d, J = 7 Hz), 6.91-7.06 (2 H, m), 7.10 to 7.25 (4H, m), 7.32 (1 H, m), 8.27 (1 H, s, indole NH)

Example 2—A: 11

 Production of 2- [3- (7-ethynindole-1-yl) -1-2-propylamino] -1- (1R) -1- (3-chlorophenyl) ethanol

 (R)-(3-chlorophenyl) oxysilane and 3- (2-aminopropyl) -17-ethoxyindole obtained in Reference Example 3 were reacted and treated in the same manner as in Example 11A. The desired product (oil) is obtained.

MS (m / z): 373 (MH ⁺ )

Examples 3-12: Instead of 3- (2-aminopropyl) -17-methoxyindole in Example 1, using the corresponding indole prepared in Reference Examples 2 and 4-12, The reaction and treatment were carried out in the same manner as in the production method (a) of Example 1 to obtain the compounds shown in Table 9. Table 9

実施例 13——

Example 13

Preparation of 2- [3- (6-carboxymethoxyindole- _3- yl) -1-2-propylamino]-( _3- chlorophenyl) ethanol sodium salt 0.42 g of the compound of Example 7 and 0.3 g of sodium hydroxide The methanol aqueous solution After adding 9 ml of the liquid (methanol: water = 2: 1), heat the mixture for 4 hours. Then, after leaving at 0 ° C for 2 hours, the precipitate is removed to obtain 0.24 g of the target product as a 1-hydrate.

 236-242 ° C

Example 14: 11

 Preparation of 2- [3- (7-Methoxycarbonylmethoxindol-1-3-yl) -2-propylamino] -1 (1R) -11- (3-chlorophenyl) ethanol

 Reaction was carried out in the same manner as in Example 11-A using (R)-(3-chlorophenyl) oxysilane and 31- (2-aminopropyl) -17-methoxycarbonylmethindole obtained in Reference Example 13 above. · The desired product (oil) is obtained by processing.

MS (m / z): 17 (MH ⁺ )

¹ H- NMR spectrum _{(CDC 1 3): 1.13 (} . 3H.d J = 6Hz, CH CH 3) .2.62 (1 Hd J = 12, 8 Hz), 2.77~ 3.13 (4 H, m) , 3. 8 l (3H, s , C0 2 CH 3), 4.47~4.68 (lH, m, CHOH) .4.75 (2 H, s, OCH 2), 6.57 (1 H, d, J = 8 Hz) , 6.92 to 7.06 (2H, m), 7.11 to 7.36 (5H, m), 8.77 (lH, s, indole NH)

Example 15:

 Preparation of 2- [3- (7-carboxymethoxyindole-1-yl) -1-2-propylamino] -1 (1R) -11- (3-chlorophenyl) ethanol: 1 Compound of Example 14 and hydroxylation Sodium is added to an aqueous methanol solution (methanol: water = 2: 1), and the reaction is carried out in the same manner as in Example 13 to obtain the desired product.

MS (m / z): 403 (MH ⁺ ) Example 16 (tablet manufacturing method): 11

 According to a conventional method, the following ingredients are mixed, granulated, and compression-molded to prepare 100 tablets of 100 mg tablets.

 5 g of the compound of Example 1

 25 g corn starch

 Lactose 54 g

 Microcrystalline cellulose 1 1 g

 Hydroxypropyl cellulose 3 g

 Light gay anhydride 1

 Magnesium stearate 1

Industrial applicability

The compounds of the present invention, pharmaceutical mammals, including humans, are particularly useful as / [delta] ₃ Adorenarin receptor stimulants, are applicable to the treatment, such as diabetes and obesity.

Sequence list SEQ ID NO: 1

Array length: 4 7

Sequence type: nucleic acid

Number of chains: double strand

 Topology: linear

Sequence type: Other nucleic acids Chemical synthesis D N A

Other information: There is a complementary strand in the 5th to 4th base sequence, and the complementary strand has TCG G as the 44th to 47th base sequence.

Array

 AGCTCCTGCA GGCGCGCCGA TATCTCGAGC GGCCGCGGTA CCA 43 SEQ ID NO: 2

Array length: 2 7

Sequence type: nucleic acid

Number of chains: 1 strand

 Topology: linear

Sequence type: Other nucleic acids Chemical synthesis D N A

Antisense: No

Array

 CCACCTGCAG GTGATTTGGG AGACCCC 27 SEQ ID NO: 3

Array length: 2 7

Sequence type: nucleic acid

Number of chains: 1 strand Topology: linear

Sequence type: Other nucleic acids Chemical synthesis D N A

Antisense: Yes

Array

 TTCTCGAGCC GGGGAATCCC ATGGGAC 27 SEQ ID NO: 4

Array length: 2 9

Sequence type: nucleic acid

Number of chains: 1 strand

 Topology: linear

Sequence type: Other nucleic acids Chemical synthesis D N A

Launch Sense: No

Array

 ACACCTGCAG GTGAGGCTTC CAGGCGTCC 29

H [: system

Array length: 2 9

Sequence type: nucleic acid

Number of chains: 1 strand

 Topology: linear

Sequence type: Other nucleic acids Chemical synthesis D N A

Antisense: Yes

Array

 TGTAAGCTTC TGCTTTACAG CAGTGAGTC 29

Claims

Scope of claim Indole derivative represented by the following general formula [I] or a salt thereof _c

[In the formula, represents a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or the following (a) Do you mean to (selected from Ru group, with R ₂ to form a Mechirenjiokishi group, the methylene Njiokin group may be substituted with a carboxyl group or a lower alkoxycarbonyl group.  (a) group represented by the formula X-Ra  (Where X is 0, S or NH, Ra is a hydrogen atom or a lower alkyl group, provided that when X is S, Ra is a lower alkyl group)  R b (b) a group represented by the formula [0 (CH ₂ ) m—CH] n—Rbb  (Where Rb is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a carboxyl group, Rbb is a lower alkoxycarbonyl group or a carboxyl group, in is an integer of 0 to 3, and n is an integer of 0 or 1. is there) (c) a group represented by formula 1 0 (CH ₂ ) p—Rc (Where Rc is a lower alkanoyl group, a hydroxyl group, a cyano group, a phenyl group, a mono- or di-lower alkylaminocarbonyl group, or o  II — P-OR _A OR _A (Where _RA is a hydrogen atom or a lower alkyl group) Where p is an integer from 1 to 4) (d) a group represented by the formula: Y— (CH ₂ ) q—Rd  (Where Y is NH or S, Rd is a carboxyl group or a lower alkoxycarbonyl group, and q is an integer of 1-4) R ₂ represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a hydroxy group, a hydroxy group, a lower alkoxy group, or the same group as in the above-mentioned) or (c); Together with the above methylenedioxy group, and the methylenedioxy group may be substituted with a carboxyl group or a lower alkoxycarbonyl group; R ₃ represents a hydrogen atom or a lower alkyl group,  W is a compound of the following formula (II) bonded to the 2- or 3-position of the indole ring of the general formula (I) R ₄ CH-CH ₂ -NH-CH-CH ₂ ― [II] OH R ₅ (Where R ₄ is a halogen atom or a trifluoromethyl group, and is a lower alkyl group) Means a group represented by 2. The following general formula [I_a] R _{4 f I. A ]}

(Wherein R !, R ₂ , R ₃ , R ₄ and R ₅ are the same as those described in claim 1) or a salt thereof. 3. The indole derivative or a salt thereof according to claim _{2, wherein} is bonded to the 5, 6 or 7 position of the indole ring, and R ₂ is a hydrogen atom. 4. Claim ₂ wherein R ₂ is a group other than a hydrogen atom, and one of R and R ₂ is bonded to the 6-position of the indole ring, and the other is bonded to the 7-position. Or a salt thereof.  5. is a lower alkyl group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a di-lower alkylaminosulfonyl group substituted with a hydroxy group, or the following (a), (bl), (c-11) and ( d)  (a) group represented by the formula X-Ra  (Where X and Ra are the same as described in claim 1)  Rb— 1 (b-1) expression one [0 (CH ₂₎ m- CH] n- group represented by Rbb  (Where Rb-1 is a hydrogen atom or a lower alkyl group, and Rbb, m and n are the same as described in claim 1) (c-1) Group represented by the formula —0 (CH ₂ ) p—Rc—1  (Where Rc-1 is a lower alkanoyl group, a phenyl group or a mono-lower alkylaminocarbonyl group, and p is the same as described in claim 1) (d) a group represented by the formula: Y— (CH ₂ ) q—Rd (Where Y, Rd, and q are the same as described in claim 1) A group selected from  R 2 is a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted by a hydroxy group, a hydroxy group, a lower alkoxy group, or the same group as the above (b-1) or ((: -1)) Yes, _3. The indole derivative according to claim 2, wherein R ₃ , R ₄ , and R ₅ are the same as those described in claim 1, or a salt thereof. 6. is a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group, a phenyl lower alkoxy group or a di-lower alkylaminosulfonyl group, R ₂ is a hydrogen atom, a halogen atom , A lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkoxy group, a carboxy lower alkoxy group or a phenyl lower alkoxy group, R ₃ is a hydrogen atom, R ₄ is a halogen atom, and R ₅ is a methyl group 3. The indole derivative or a salt thereof according to claim 2, which is: 7 is a methoxy group, an ethoxyquin group, a methyl group, a methoxycarbonyl group, a methoxycarbonyl methoxy group, a carboxymethoxy group, a benzyloxy group, or a dimethylaminosulfonyl group; R ₂ is a hydrogen atom or a methoxy group; 7. The indole derivative or a salt thereof according to claim 6, wherein ₃ is a hydrogen atom, R 4 is a chlorine atom, and R ₅ is a methyl group. Is bonded to the 6- or 7-position of the indole ring, a methoxy group, an ethoxyquin group, a methoxycarbonyl group, a methoxycarbonylmethoxy group or a carboxymethoxy group; R ₂ and R ₃ are hydrogen atoms; 8. The indole derivative or a salt thereof according to claim 7, wherein R ₄ is a salt atom and R 5 is a methyl group. 9. 2- [3- (7-Methoxyindole-3-yl) -1- 2-propylamino] 1-1- (3-chlorophenyl) ethanol or a salt thereof. 1 0.2— [3- (7-Methoxyindole-13-yl) -1-2-propylamino] -11- (3-chlorophenyl) ethanol optical isomer or its isomer 1 1.2- [3- (7-Ethoxyindole-1-yl) -1-propylamino] 1-1 (3-chlorophenyl) ethanol or a salt thereof.  12.2— [3- (7-Ethoxyindole-1-yl) -1--2-propylamino] -11- (3-chlorophenyl) ethanol optical isomer or its isomer Affile  13.2- [3- (7-Methoxycarbonylmethoxyindole-1-3-yl) -1-2-propylamino] -11- (3-chlorophenyl) ethanol or a salt thereof.  14.2— [3- (7-Methoxycarbonylmethoxyindole-13-yl) -1-2-propylamino] -11- (3-chlorophenyl) ethanol isomer or its salt.  15.2- [3- (7-Carboxymethoxyindole-1-3-inole) -12-propylamino] 1-1- (3-chlorophenyl) ethanol or a salt thereof.  16.2— [3- (7-Carboxymethoxyindole-13-yl) -12-propylamino] -11- (3-chlorophenyl) ethanol optical isomer or a salt thereof. 1 7. indole derivative or / 3 ₃ Adorena phosphate receptor stimulant, characterized by containing these physiologically acceptable salt thereof as an active ingredient in the range first claim of claim.  1 8. An agent for treating diabetes, comprising the indole derivative according to claim 1 or a physiologically acceptable salt thereof as an active ingredient. 1 9. The indole derivative according to claim 1 or a physiologically acceptable derivative thereof For obesity, characterized by containing a salt acceptable to the skin as an active ingredient 20. A method for treating a diabetic disease in a mammal, comprising administering the indole derivative according to claim 1 or a physiologically acceptable salt thereof to the mammal.  21. A method for treating obesity disease in a mammal, comprising administering the indole derivative according to claim 1 or a physiologically acceptable salt thereof to the mammal.  22. Use of the indole derivative according to claim 1 or a physiologically acceptable salt thereof for the treatment of diabetes in a mammal.  23. Use of the indole derivative or the physiologically acceptable salt thereof according to claim 1 for the treatment of obesity disease in mammals.  24. A pharmaceutical composition comprising the indole derivative according to claim 1, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier for a pharmaceutical preparation.  25. A method for producing an indole derivative represented by the formula [I] or a salt thereof according to claim 1, wherein the method comprises the following formula [I I I] Hif CH ₂ [ΠΙ]  0 (Wherein, R ₄ is the same as described in claim 1) The compound represented by the following formula (IV)

[Wherein Ri, R ₂ , R ₃ and R ₅ are the same as those described in claim 1] or a salt thereof.  26. The following formula [I-b]

[In the formula, 'represents a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or the following (a ) ', (B), (c) and (d)', or may form a methylenedioxy group together with R ₂ , wherein the methylenedioxy group is a carboxyl group or a lower alkoxycarbonyl group. May be substituted.  (a) 'Formula X'—group represented by Ra  (Where X 'is 0 or S, and Ra is the same as described in Claim 1. However, when X' is S, Ra is a lower alkyl group.)  Rb (b) a group represented by the formula [0 (CH ₂ ) ra—CH] n—Rbb  (Where Rb, Rbb, in and n are the same as those described in claim 1) (c) a group represented by formula 1 0 (CH ₂ ) p—Rc  (Where Rc and p are the same as described in claim 1) (d) 'Formula I Y' — (CH ₂ ) q—Rd group  (Where Y 'is S, Rd and q are the same as described in claim 1) R ₂ , R ₃ , R ₄ and R ₅ are the same as described in claim 1) A method for producing a compound represented by the formula or a salt thereof, comprising the following formula (V)

(Wherein, R ₄ is the same as described in claim 1) A compound represented by the following formula !: VI)

(In the formula, 'is the same as above, R ₂ , R ₃ and R ₅ are the same as described in claim 1) And reacting the compound represented by the formula (1) under the conditions of the conventional method.  2 7. The following formula [I-c] [ I c]

Wherein R is a lower alkyl group which may be substituted with a hydroxy group, a phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or It may mean a group selected from (a) or (c) ", or may form a methylenedioxy group together with R ₂ ".  (a) group represented by the formula X-Ra (Where X and Ra are the same as described in claim 1) (c) a group represented by “formula 0 (CH ₂ ) p—Rc”  (Where Rc "is a hydroxyl group, a phenyl group, or a compound represented by the following formula:

(Where _RA is a hydrogen atom or a lower alkyl group), and p is the same as defined in claim 1) R ₂ "represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a hydroxy group, a hydroxy group, a lower alkoxy group, or a group represented by the above (c)"; It may form a methylenedioxy group together with R. R ₃ , R ₄ and R ₅ are the same as described in claim 1) A method for producing a compound represented by the formula or a salt thereof, comprising the following formula !: VII]

Wherein R and R ₂ ″ are the same as above, and R ₃ , R ₄ and R ₅ are the same as described in claim 1 A method characterized by passing a compound represented by the formula: